Journal of Ethnopharmacology 171 (2015) 247–263

Contents lists available at ScienceDirect

Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep

Review

Medicinal uses, phytochemistry and pharmacology of the genus Dictamnus (Rutaceae) Mengying Lv a,b, Ping Xu c, Yuan Tian a,b, Jingyu Liang d, Yiqiao Gao a,b, Fengguo Xu a,b, Zunjian Zhang a,b,n, Jianbo Sun d,nn a

Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, China State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China c Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China d Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China b

art ic l e i nf o

a b s t r a c t

Article history: Received 5 February 2015 Received in revised form 28 May 2015 Accepted 29 May 2015 Available online 9 June 2015

Ethnopharmacological relevance: Seven species from the genus Dictamnus are distributed throughout Europe and North Asia and only two species grow in China. One is Dictamnus dasycarpus Turcz., which could be found in many areas of China and has been recorded in Chinese Pharmacopoeia. The other is Dictamnus angustifolius G. Don ex Sweet, which is only present in Xinjiang province and has been used as an alternative for Dictamnus dasycarpus in the local for the treatment of rheumatism, bleeding, itching, jaundice, chronic hepatitis and skin diseases. The present paper reviewed the traditional uses, phytochemistry, pharmacology and toxicology of the genus Dictamnus. Materials and methods: Information on the Dictamnus species was collected from classic books about Chinese herbal medicine and globally accepted scientific databases including PubMed, Elsevier, ASC, Scopus, Google Scholar, Web of Science, CNKI and others. Results: About 170 chemical compounds, which include quinoline alkaloids, limonoids, sesquiterpenes, coumarins, flavonoids and steroids, have been isolated from the genus Dictamnus. The characteristic and active constituents of Dictamnus species are considered to be quinoline alkaloids and limonoids, which exhibited a broad spectrum of biological activities such as anti-cancer, anti-inflammation, anti-microbe, anti-platelet-aggregation, vascular-relaxation, anti-insect, anti-HIV, anti-allergy and neuroprotection. Moreover, quinoline alkaloids and limonoids could be used as quality control markers to distinguish different species from the genus Dictamnus. However, there were also some reports on the toxic hepatitis and phototoxic effect of Dictamnus species, and the related research needs to be further studied. Conclusion: In this review, we summarized the chemical constituents, pharmacology, quality control and toxicology of the species from genus Dictamnus. Phytochemical investigations indicated that quinoline alkaloids and limonoids were the major bioactive components with potential cytotoxic, neuroprotective, anti-inflammatory, antimicrobial, anti-platelet-aggregation and vascular relaxing activities. These two kinds of compounds have attracted great interests in the past few years and may have great potential to be new drug lead compounds. & 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Dictamnus Phytochemistry Pharmacology Toxicology

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medicinal properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Quinoline alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Limonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Sesquiterpenes and its glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

248 248 252 252 253 254

n Corresponding author at: Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), China Pharmaceutical University, Nanjing 210009, China. Tel./fax: þ 86 25 83271454. nn Corresponding author at: Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Tel./fax: þ 86 25 83271415. E-mail addresses: [email protected] (Z. Zhang), [email protected] (J. Sun).

http://dx.doi.org/10.1016/j.jep.2015.05.053 0378-8741/& 2015 Elsevier Ireland Ltd. All rights reserved.

248

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

3.4. Flavones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Coumarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Steroids and triterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Other compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.8. Essential oils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Anti-cancer activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Anti-inflammatory, anti-allergic and immunological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Anti-microbial and anti-HIV activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Anti-platelet-aggregation and vascular-relaxing activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Anti-insect activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Antidepressant and neuroprotective activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Antimutagenic activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. Antifertility activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9. Antioxidant activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Quality control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

254 254 254 254 254 255 255 256 257 258 259 259 260 260 260 261 261 261 261 261

1. Introduction Species (Table 1) from the genus Dictamnus, which belongs to the family Rutaceae, are distributed throughout Europe and North Asia (Sun et al., 2013b). Among them, Dictamnus dasycarpus Turcz and Dictamnus angustifolius G. Don ex Sweet which root barks both called Cortex Dictamni (Chinese name 白鲜皮) in China, have long been used in Traditional Chinese Medicine for the treatment of rheumatism, bleeding, itching, jaundice, chronic hepatitis and skin diseases (Wu et al., 1999; Chinese Herbalism Editorial Board., 1999). The root bark of Dictamnus dasycarpus, which grows in many areas of China such as Heilongjiang, Jilin, Liaoning, Ningxia and Gansu provinces, is recorded in various versions of Chinese Pharmacopoeia (中国药典) and is also used as herbal medicines in Korea and Japan (Kim et al., 2013). The root bark of Dictamnus angustifolius, which occurs only in Xinjiang province, was recorded in Zhong Hua Ben Cao (中华本草) and has been used as an alternative for Dictamnus dasycarpus in the zone (Sun et al., 2013a). With increasing attention paid to the chemical constituents of medicinal herbs, phytochemical studies have been performed on Dictamnus species. Currently, about 170 chemical compounds have been isolated and identified from Dictamnus species, with approximately 92 compounds from Dictamnus dasycarpus and 55 compounds from Dictamnus angustifolius. They are limonoids, quinoline alkaloids, sesquiterpenes, coumarins, flavonoids, steroids and triterpenes. As the characteristic and active constituents in Dictamnus species, limonoids and quinoline alkaloids possess wide-reaching biological activities, including anti-cancer, anti-inflammatory, antimicrobial, anti-platelet-aggregation, vascular-relaxing, anti-insect, anti-HIV, immunosuppressing, neuroprotective, antioxidant and

mutagenic activities (Wang et al., 2013a, 2013b). In recent years, more and more investigations on Dictamnus dasycarpus and Dictamnus angustifolius have been conducted, and the genus Dictamnus has gradually been paid more attention because of its medicinal value. In the present review, advances in investigation of medicinal uses, phytochemistry, pharmacology and toxicology of Dictamnus species are reviewed, which aims to promote the development of new drugs and better utilization of different species.

2. Medicinal properties With a wide spectrum of biological and pharmacological effects, Dictamnus dasycarpus has been traditionally used in China with the dried root bark as the medicinal part. The root bark of Dictamnus dasycarpus was early recorded in Shen Nong Ben Cao Jing (神农本草 经), and was listed as “medium grade”. In this monograph, the root bark of Dictamnus dasycarpus is bitter in flavor, cold in nature, and useful for headache, jaundice, cough, edema and pain in vagina, strangury and rheumatic arthralgia. In Ben Cao Gang Mu (本草纲目), the most famous medicinal book in China written by Li Shizhen (李时 珍), the root bark of Dictamnus dasycarpus was thought to be innocuous and could be used for the treatment of headache, jaundice, cough, urticarial, scabies, etc. Since its listing in Ben Cao Gang Mu, the root bark of Dictamnus dasycarpus has been recorded in many other classical medicinal books in China (Chinese Herbalism Editorial Board., 1999). Because of its fabulous and definite clinical effects, the root bark of Dictamnus dasycarpus was listed in Chinese Pharmacopoeia. In

Table 1 Species in Dictamnus (Rutaceae). Species Dictamnus Dictamnus Dictamnus Dictamnus Dictamnus Dictamnus Dictamnus

albus L. angustifolius G.Don ex Sweet caucasicus (Boiss.) Fisch. Ex Grossh. dasycarpus Turcz. gymnostylis Steven hispanicus Webb ex Willk. tadshikorum Vved.

Habitats

Distribution areas

Open forests, shrubby formations, open stony slopes Steppe meadows, shrubby formations Steppes, shrubby formations, open forests Open forests, shrubby formations, open stony slopes Open forests, shrubby formations Open oak and pine forests, shrubby formations Herbaceous and shrubby slopes in mountains

Europe W Siberia and C Asia Caucasus and NW Iran E. Siberia, Mongolia, N. China, Korea SE Europe and Caucasus E Iberian Peninsula C Asia

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

249

Table 2 The compounds isolated from Dictamnus species. Classification Quinoline alkaloids

No. Chemical compound

Akhmedzhanova et al. (1978), Du et al. (2005) and Kim et al. (1997)

2 3

Zhao et al. (1998b) Asatiani et al. (1971), Nam et al. (2005) and Sun et al. (2013b)

6

7 8 9 10 11 12 13 14 15 16 17

18 19 20 21

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

D. dasycarpus D. angustifolius D. albus Confusameline D.dasycarpus Robustine D. angustifolius D. albus D. caucasicus Evolitrin D.albus γ-Fagarine D. dasycarpus D. angustifolius Haplopine D.albus D. angustifolius Kokusaginin D.albus D.caucasicus Maculosidin D.albus D.caucasicus Skimmianine D. dasycarpus 5-Methoxydictamnine D. angustifolius 5-Hydroxy-4,8-dimethoxy-furoquinoline D. angustifolius Haploperine D. angustifolius O-Ethylnordictamnine D. dasycarpus O-Ethylnor-γ-fagarine D. dasycarpus O-Ethylnorskimmianine D. dasycarpus Sonminine D. angustifolius Isodictamnine D.albus D. angustifolius Dictangustine A D. angustifolius 8-Hydroxy-9-methyl-furo[2,3-b]quinolin-4(9H)-one D. dasycarpus Isopteleine D. angustifolius Iso-γ-fagarine D. dasycarpus D. angustifolius Isomaculosidine D. dasycarpus Platydesmine D. dasycarpus Myrtopsine D. dasycarpus Deacetyldubinine D. dasycarpus 7,8-Dimethoxyplatydesmine D. dasycarpus (S)-7,8-Dimethoxymyrtopsine D. dasycarpus (R)-7,8-Dimethoxymyrtopsine D. dasycarpus (-)-1’,2-Anhydro-7,8-dimethoxyplatydesmine D. dasycarpus (3R)-3,4-Dihydro-5,8,9-trimethoxy-2,2-dimethyl-2H-Pyrano[2,3- D. dasycarpus b]quinolin-3-ol 3-Chloro-8,9-dimethoxygeibalansine D. dasycarpus 5,9-Dimethoxy-2,2-dimethyl-2H-Pyrano[2,3-b]quinoline D. dasycarpus Dasycarine D. dasycarpus Preskimmianine D. dasycarpus 2(1H)-Quinolinone D. dasycarpus 2(1H)-Quinolinone-β-D-Glu D. dasycarpus Carbostyril D.albus 3-[1β-Hydroxy-2-(β-D-glucopyranosyloxy)-ethyl]-4-methoxy-2 D. dasycarpus (1H)-quinolinone N-Methylpreskimmianine D. angustifolius N-Methylflindersine D. angustifolius Rutacridon D. hispanicus Ribalinidine D. hispanicus 7-O-Methylribalinidine D. hispanicus Dubamine D. angustifolius

Ref.

1 Dictamnine

4 5

Limonoids

Plant source

45 Limonin

D. dasycarpus

Storer and Young (1973) Du et al., 2005, Yang et al. (2011), Li et al. (2008), Sun et al. (2013a) and Wu et al. (1994) Nam et al. (2005) and Woo and Kang (1985)

(Jeong et al. (2006) and Schempp et al. (2006) Jeong et al. (2006) and Schempp et al. (2006) Jeong et al. (2010) and Yoon et al. (2012) Sun et al. (2013b) Sun et al. (2013b) Sultanov and Yunusov (1969) Lin and Shieh (1986) Lin and Shieh (1986) Lin and Shieh (1986) Sun et al. (2013b) Akhmedzhanova et al. (1978) and Gellert et al. (1971)

Wu et al. (1999) Chang et al. (2002) Sun et al. (2013a) Wu et al. (1999) and Yoon et al. (2012)

Yoon et al. (2012) Wu et al. (1994) Yang et al. (2011) Kim et al. (1997) Wu et al. (1994) Wu et al. (1994) Wu et al. (1994) Chen et al. (2000) Chen et al. (2000) Chen et al. (2000) Chen et al. (2000) Du et al. (2005) Wu et al. (1999) and Yoon et al. (2012) Yoon et al. (2012) Yoon et al. (2012) Chen et al. (2000) Yoon et al. (2012) Sun et al. (2013b) Sun et al. (2013b) Gonzalez et al. (1977) Gonzalez et al. (1977) Gonzalez et al. (1977) Sultanov and Yunusov (1969) Wu et al. (1999) and Yoon et al. (2010)

250

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

Table 2 (continued ) Classification

No. Chemical compound

46 47 48 49

Limonoic acid Rutaevin Rutaevin acetate Limonexic acid

50 Limonin diosphenol

51 Obacunone

52 7-Obacunyl acetate 53 Dihydroobacunone 54 Dictangustone E 55 Nomilin 56 7-Acetoxyldihydronomilin 57 Kihadanin B 58 Obacunone acid 59 Dictangustone A 60 Dictangustone C 61 Dictangustone D 62 Isoobacunoic acid 63 Dictangustone B 64 Dictangustone F 65 Fraxinellone

66 Dasycarpol 67 Fraxinellonone

68 69 70 71 72

Isofraxinellone (3R)-Isobenzofuranone Dasylactone A Dasylactone B (1,4,8a)-( 7)-1-(3-Furanyl)-1,4,6,7,8,8a-hexahydro -4-hydroxy5,8a-dimethyl-3H-2-Benzopyran-3-one 73 Dictamdiol

74 Dictamdiol A 75 Dictamdiol B 76 1-(3-Furanyl)-1,4,6,7,8,8a-hexahydro-4,6-dihydroxy-5,8a -dimethyl-3H-2-Benzopyran-3-one 77 Isodictamdiol 78 Isodictamdiol A

Sesquiterpenes and its glycosides

Plant source D. angustifolius D. dasycarpus D. dasycarpus D. dasycarpus D. angustifolius D. dasycarpus D. angustifolius D. dasycarpus D. angustifolius D. dasycarpus D. dasycarpus D. angustifolius D. angustifolius D. dasycarpus D. dasycarpus D. angustifolius D. angustifolius D. angustifolius D. angustifolius D. angustifolius D. angustifolius D. angustifolius D.albus D. dasycarpus D. angustifolius D. dasycarpus D. dasycarpus D. angustifolius D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D.radicis D. dasycarpus D. angustifolius D. dasycarpus D. dasycarpus D. dasycarpus

Ref.

Yang et al. (2011) Li et al. (2008) and Wang et al. (1992) Jeong et al. (2006) Wu et al. (1999) Du et al. (2005) and Wu et al. (1999)

Du et al. (2005), Jiang et al. (2006a) and Wu et al. (1999)

Jeong et al. (2006) Chen et al. (2000) Sun et al. (2015a) Lv et al. (2015a) Jeong et al. (2006) Du et al. (2005) Lv et al. (2015a) Sun et al. (2015a) Sun et al. (2015a) Sun et al. (2015a) Lv et al. (2015a) Sun et al. (2015a) Sun et al. (2015a) Kim et al. (1997), Lu et al. (2013) and Sun et al. (2013a)

Zhao et al. (1998b) Jiang et al. (2006a), Wu et al. (1999) and Yoon et al. (2008) Zhao et al. (1998b) Zhao et al. (1998b) Yang et al. (2011) Yang et al. (2011) Nam et al. (2005) Hu et al. (1989) and Jiang et al. (2006b)

Yoon et al. (2008) Yoon et al. (2008) Jeong et al. (2006)

79 Calodendrolide 80 9α-Hydroxyfraxinellone-9-O-β-D-glucoside 81 Dictamnusine

D. dasycarpus D. angustifolius D. dasycarpus D. dasycarpus D. dasycarpus

Zhao et al. (1998b) Yoon et al. (2008) Yoon et al. (2008)

82 2H-1,4-(Epoxymethano)naphthalen-4,8-diol

D. dasycarpus

Zhao et al. (1998a)

83 84 85 86

D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. angustifolius D. angustifolius D. dasycarpus D. dasycarpus

Guo et al. (2012a) Zhao et al. (1998a) Zhao et al. (1998b) Sun et al. (2013b) and Zhao et al. (1998b)

Dictamnadiol 2H-1,4-(Epoxymethano)naphthalen-4-ol β-Elemol Dictamnol

87 Radicol 88 β-D-glucopyranoside 89 Dictamnoside A

Zhao et al. (2007) Sun et al. (2013a)

Sun et al. (2013b) and Zhao et al. (1998b) Zhao et al. (1998a) Chang et al. (2001)

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

251

Table 2 (continued ) Classification

Flavones

No. Chemical compound

Plant source

Ref.

90 91 92 93 94 95 96 97 98 99 100 101 102

Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside Dictamnoside

D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D.albus D. dasycarpus D. dasycarpus D. dasycarpus

Zhao et al. (1998a) Zhao et al. (1998a) Zhao et al. (1998a) Zhao et al. (1998a) Zhao et al. (2001) Zhao et al. (2001) Jeong et al. (2006) Jeong et al. (2006) Jeong et al. (2006) Storer and Young (1973) Jeong et al. (2006) Zhao et al. (2001) Zhao et al. (1998a)

103 104 105 106

Wogonin Luteolin 4H-1-Benzopyran-4-one Quercetin

D. dasycarpus D. dasycarpus D. dasycarpus D. angustifolius D.albus D. angustifolius D.albus D.albus D.albus D.albus D.albus D.albus D.albus D.albus D.albus D. angustifolius D.albus D.albus D.albus D. angustifolius D.albus

Du et al. (2005) Wang (2006) Wang (2006) Komissarenko et al. (1984)

B C D E F G H I J K L M N

107 Luteolin 3’-methyl ether

108 109 110 111 112 113 114 115 116

Luteolin 7,3’-dimethyl ether Kaempferol-3,5,7-trimethyl ether Quercetagetin-3,6-dimethyl ether (axillarin) Isorhamnetin Dihydroquercetin-7,3’-dimethyl ether 3’-Methylorobol Luteolin 3’,4’-dimethyl ether-7-O-β-D-methylglucuronide Diosmin Isoquercetin

117 Kaempferol-3-O-β-D-rutinoside 118 Isoquercitrin 119 Rutin

120 Isorhamnetin-3-O-β-D-rutinoside Coumarins

121 2H-1-Benzopyran-2-one 122 Umbelliferone 123 Esculetin 124 Scopoletin 125 Herniarin 126 Scoparone 127 Psoralene 128 Xanthotoxin

129 Bergaptene 130 Isoimpinellin 131 2,2-Dimethylchromenocoumarin 132 Angustifolin 133 Imperatorin 134 Isoimperatorin 135 136 137 138 139 Steroids and triterpenes

Bjacangelicin Heliettin Rutamarin Auraptene 2H-1-Benzopyran-2-one

140 β-Sitosterol

D. gymnostylis D. albus D. angustifolius D. angustifolius D. angustifolius D. angustifolius D. angustifolius D. albus D. angustifolius D. angustifolius D. angustifolius D. hispanicus D. angustifolius D. angustifolius D. angustifolius D. hispanicus D. hispanicus D. hispanicus D. albus D. hispanicus D. dasycarpus D. angustifolius D. hispanicus

Komissarenko et al. (1984) and Souleles (1989b)

Komissarenko et al. (1984) and Souleles (1989b) Souleles (1989a) Souleles (1989a) Ivanova et al. (2004) Souleles (1989a) Grabarczyk (1964) Komissarenko et al. (1984) and Souleles (1989b) Grabarczyk (1964) Grabarczyk (1964) and Komissarenko et al. (1984)

Souleles (1989a) Renner (1962) (Bodalski and Malcher (1964), Ivanova et al. (2004) and Komissarenko et al. (1984) Ivanova et al. (2004) Denisova and Belenovskaya (1972) Jeong et al. (2006) Komissarenko et al. (1984) (Komissarenko et al., 1984) (Wu et al., 1999) (Wu et al., 1999) (Komissarenko et al., 1984) (Jeong et al., 2006; Komissarenko et al., 1984)

(Komissarenko et al., 1984) (Komissarenko et al., 1984) (Gonzalez et al., 1977) (Wu et al., 1999) (Komissarenko et al., 1984; Weryszko-Chmielewska et al., 1998) Komissarenko et al. (1984) Gonzalez et al. (1977) Gonzalez et al. (1977) Gonzalez et al. (1977) Jeong et al. (2006) and Reisch et al. (1967) Gonzalez et al. (1977) Akhmedzhanova et al. (1978), Du et al. (2005) and Gonzalez et al. (1977)

252

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

Table 2 (continued ) Classification

No. Chemical compound

Plant source

Ref.

141 142 143 144 145

D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. angustifolius D. dasycarpus D. dasycarpus D. angustifolius D. dasycarpus D. dasycarpus D. hispanicus D. hispanicus D. angustifolius

Zhao et al. (1998b) Li et al. (2008) Wu et al. (1994) Wu et al. (1994) Wu et al. (1999)

7α-Hydroxysitosterol Daucosterol Stigmasterol 6β-Hydroxystigmast-4-en-3-one Stigmast-4-ene-3,6-dione

146 Cholest-7-en-3β-ol 147 Progesterone 148 Lup-20(29)-en-3β, 6α-diol

Other compounds

149 150 151 152 153

Pregnenolone Pregnenolone acetate β-Amyrin α-Amyrin Oleanic acid

154 155 156 157 158 159 160 161

Aasycarpusenester A Dasycarpusester B Dasycarpusacid 2-Cyclohexene-1,2-dimethanol 3-Cyclohexene-1,2-dimethanol Dictamnaindiol Dasycarpuside B Dictafolin A

162 Dictafolin B 163 2-Methoxy-4-acetylphenol 1-O-alpha -rhamnopyranosyl-(1”– 4 6’)-beta-glucopyranoside 164 2-Methoxy-4-hydroxymethylphenol 1- O-alpha -rhamnopyranosyl-(1”–46’)-beta –glucopyranoside 165 2-Methoxy-4-(8-hydroxyethyl)-phenol 1-O-alpharhamnopyranosyl-(1”–4 6’)-beta-glucopyranoside 166 Dasycarpuside A 167 Ethanone 168 Cnidioside A 169 Methylcnidioside A 170 Cnidioside B 171 Methylcnidioside B

Wu et al. (1994) Wu et al. (1994) Lv et al. (2015a) Takeuchi et al. (1993) Takeuchi et al. (1993) Gonzalez et al. (1977) Gonzalez et al. (1977) Lv et al. (2015a)

D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. dasycarpus D. angustifolius D. angustifolius D. dasycarpus

Guo et al. (2012b) Guo et al. (2012b) Guo et al. (2012b) Zhao et al. (1998b) Zhao et al. (1998b) Guo et al. (2012a) Chang et al. (2002) Wu et al. (1999)

D. dasycarpus

Chang et al. (2002)

D. dasycarpus

Chang et al. (2002)

D. D. D. D. D. D.

Chang et al. (2002) Chang et al. (2002) Ivanova et al. (2004) Ivanova et al. (2004) Ivanova et al. (2004) Ivanova et al. (2004)

dasycarpus dasycarpus albus albus albus albus

Wu et al. (1999) Chang et al. (2002)

Note: Compounds in this table are numbered and these numbers are used throughout the text, between parentheses, i.e. (1), and figures to simplify references.

Korea, people use this plant mainly for the treatment of skin diseases such as eczema, atopic dermatitis and psoriasis (Kim et al., 2013). In Japan, the root bark of Dictamnus dasycarpus has been used to treat jaundice and rheumatism in addition to skin diseases because of its capability of clearing away heat and eliminating dampness. The other species, Dictamnus angustifolius, only distributes in Xinjiang province of China and has been used as an alternative for the root bark of Dictamnus dasycarpus to treat similar diseases in local areas (Wu et al., 1999). Dictamnus angustifolius was listed in Zhong Hua Ben Cao as the material source of Cortex Dictamni together with Dictamnus dasycarpus (http://www.zysj.com.cn). Cortex Dictamni is deemed as a febrifugal and detoxicant drug and attributive to the spleen, lung, stomach and bladder meridians. It could be taken orally as water decoctions or applied externally as fine powders for the treatment of jaundice, rheumatic arthralgia and skin diseases that were resulted from cold, heat, dampness and toxin.

3. Phytochemistry Up to date, many chemical compounds (Table 2), such as quinoline alkaloids, limonoids, sesquiterpenes, coumarins, flavonoids, steroids, etc., have been isolated from genus Dictamnus. Among them, quinoline alkaloids and limonoids are considered to be characteristic and active components of Dictamnus species.

3.1. Quinoline alkaloids Quinoline alkaloids are the major components of this genus. 44 alkaloids, 1–44, were isolated from this genus. Structural characteristics of these compounds are listed as follows: (1) 31 quinoline alkaloids possess a furan ring and the rest contain other types of ring structures or have no furan rings; (2) 26 quinoline alkaloids have oxygen-containing substitutions on the benzene ring. Generally, these substitutions are methoxyl groups and hydroxyl groups, and only a small number of them have been substituted with other types of functional groups. (3) 23 quinoline alkaloids have oxygen-containing substitutions on the C-4 position. Mostly, these substitutions are methoxyl groups and only 3 of them have been substituted with ethoxyl groups or hydroxyl groups. According to the structures (Fig. 1), generally, these compounds could be further classified into furoquinoline alkaloids (compounds 1–15, 23–32, 39) and quinolone alkaloids (compounds 16–22, 33–38, 40–43). Among them, only dictamnine (1) and robustine (2) could be found in three Dictamnus species. Up to now, 25, 15, 8, 3 and 3 quinoline alkaloids have been isolated from Dictamnus dasycarpus, Dictamnus angustifolius, Dictamnus albus L., Dictamnus caucasicus (Boiss.) Fisch. ex Grossh. and Dictamnus hispanicus Webb ex Willk., respectively. Similar quinoline alkaloids have been found in other species of the Rutaceae, especially the genus Zanthoxylum, and they were also most abundant in the barks and roots of Zanthoxylum species (Sun et al., 2013b).

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

253

Fig. 1. The chemical structures of quinoline alkaloids from Dictamnus species.

Fig. 2. The chemical structure of limonin.

3.2. Limonoids Limonoids, which only occur naturally in plant species of Rutaceae and Meliaceae families, are highly oxygenated, modified terpenoids with a prototypical structure derived from a precursor with a 4,4,8-trimethyl-17-furanylsteroid skeleton (Manners, 2007). The search for limonoids started from the desire to look for the reason of bitterness in citrus. The term limonoids was derived

from limonin (45), a tetranortriterpenoid that was first isolated from Washington navel orange and was responsible for the bitterness in citrus fruits (Roy and Saraf, 2006). All naturally occurring limonoids possess a furan ring at C-17 and oxygencontaining functional groups at C-3, C-4, C-7, C-16 and C-17 (Fig. 2). The structural variations of limonoids are relatively less in species from Rutaceae than Meliaceae, and generally modifications are limited to A and B rings. It is reported that limonoids are synthesized via tripterpenoid biosynthetic pathways that start from cyclization of squalene (Roy and Saraf, 2006). Euphane or tirucallane triterpenoids, which are chemically similar and are the main characteristic chemical constituents from Rutaceae, may be the ultimate biogenetic precursors of limonoids. Through α-oxidation at double bond C-7, Wagner-Meerwein rearrangements and formation of β-substituted furan, limonoids with integral tetracyclic skeletons such as 7-acetoxyldihydronomilin (56) could be obtained (Fig. 3). Previous phytochemical studies on genus Dictamnus identified a total of 37 limonoids which could be subdivided as limonoid aglycons (Wu et al., 1999; Lv et al., 2015a; Sun et al., 2015a),

254

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

Fig. 3. Possible biosynthetic pathways of limonoids from Dictamnus species.

degraded limonoids (Sun et al., 2013a), and limonoid glucosides (Yoon et al., 2008). Dictamnus species are rich in limonoids with A/ D ring split (Fig. 4) and degraded limonoids, which are formed by losing A and B rings on limonoids with A/B/D ring split (Fig. 5). As shown in Table 2, a total of 25 and 17 limonoids have been isolated from Dictamnus dasycarpus and Dictamnus angustifolius, respectively. Only fraxinellone (65) could be found in three Dictamnus species. Limonin (45), obacunone (51), fraxinellonone (67) and dictamdiol (73) could be found in two Dictamnus species. In Chinese Pharmacopoeia, the content of obacunone (limonoid aglycon) and fraxinellone (degraded limonoid) has been used to evaluate the quality of crude drug Cortex Dictamni. 3.3. Sesquiterpenes and its glycosides Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the molecular formula C15H24. Up to now, 20 sesquiterpenes and its glycosides have been isolated from the genus Dictamnus, mostly from Dictamnus dasycarpus. Most sesquiterpenes are of the eudesmane-type and trinoruaiane-type (Fig. 6). Since sesquiterpene glycosides have large polarity, they usually isolated from the water or n-butanol phase of plant extracts. The sugar moiety, mostly β-D-Glc or β-D-Glc-(6-1)-α-Glc, often attaches to C-7 position of sesquiterpenes. 3.4. Flavones Flavones in Dictamnus species mainly exist as aglycons, with relatively low contents. 18 flavones (Fig. 7) have been isolated from genus Dictamnus, mostly from Dictamnus dasycarpus and Dictamnus albus. Only four compounds belonging to flavones have been identified from Dictamnus angustifolius.

3.5. Coumarins To date, 19 coumarins have been isolated from Dictamnus species, mainly from Dictamnus angustifolius and Dictamnus hispanicus. They are mainly simple coumarins and furocoumarins with substitutions such as methoxyl, hydroxyl and isopentene groups (Fig. 8). Only 2,2-dimethylchromenocoumarin (131) belongs to pyranocoumarins. 3.6. Steroids and triterpenes 11 steroids (Fig. 9) have been isolated from Dictamnus species, mainly from Dictamnus dasycarpus. Triterpenes are rarely found in Dictamnus species. Only two triterpenes, β-amyrin (151) α-amyrin (152) were isolated from Dictamnus hispanicus. 3.7. Other compounds What is more, many other constituents (Fig. 10) were reported to be isolated from Dictamnus dasycarpus, Dictamnus albus and Dictamnus angustifolius. 3.8. Essential oils 47 constituents (88.9% of the total oil) were identified in the essential oil obtained from the root bark of Dictamnus dasycarpus and the main compounds were syn-7-hydroxy-7-anisylnorbornene (29.4%), pregeijerene (15.5%) and geijerene (11.4%) (Lei et al., 2008). 52 compounds representing 97.2% of the total oil were identified in the essential oil from the root bark of Dictamnus angustifolius and the major components were tetramethylenecyclobutane (42.07%) and fraxinellone (19.06%) (Sun et al., 2015b).

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

255

Fig. 4. The chemical structures of limonoids from Dictamnus species.

4. Pharmacology

4.1. Anti-cancer activities

Wide clinical uses of traditional Chinese medicine Cortex Dictamni have inspired researchers to investigate its pharmacological properties and to validate the uses of different species as therapeutic remedy. Several studies showed that extracts or active compounds of Dictamnus species exhibited a wide range of pharmacological activities such as anti-cancer, anti-inflammatory, antimicrobial, antiplatelet-aggregation, vascular-relaxing, anti-insect, anti-HIV, antiallergic, immunosuppressing, neuroprotective, mutagenic and antimutagenic, antifertility and anti-oxidant activities.

Dictamnus species are rich in limonoids, obacunone (51), limonin (45), nomilin (55) and their glucosides and some aglycones inhibited chemically induced carcinogenesis and a series of human cancer cell lines, with remarkable cytotoxicity against lung, colon, oral and skin cancer in animal test system and human breast cancer cells (Roy and Saraf, 2006). In mice, limonin (45) and nomilin (55), administered by gavage or added in the diet of animals exposed to benzo[α]pyrene (BP), could remarkably inhibit forestomach and lung tumor growth (Lam et al., 1994b). The two

256

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

Fig. 5. The chemical structures of degraded limonoids from Dictamnus species.

compounds were also shown to be effective in inhibiting 7,12dimethylbenz[α]anthracene (DMBA)-induced two-stage skin carcinogenesis in mice (Lam et al., 1994a). Both limonoids have been found to increase activity of the detoxifying enzyme glutathione Stransferase (GST) and the increased enzyme activity was correlated with the ability of these compounds to inhibit chemically induced carcinogenesis in animals (Lam et al., 1994b). In hamsters, limonin (45) and nomilin (55), were tested for their effects on the development of DMBA-induced buccal pouch epidermoid carcinomas and the results suggested that limonin (45) was more effective than nomilin (55) as an inhibitor of DMBA-induced neoplasia (Miller et al., 1989). In subsequent hamster studies, the synthetically derived compound of deoxylimonoic acid showed no antitumor activity, indicating the importance of C-14,15 expoxide and an intact B-ring in biological activities of limonoids (Lam et al., 1994b). Two limonoid aglycones, limonin (45, containing 0.02% or 0.05% w/w in diet) and obacunone (51, containing 0.02% or 0.05% w/w in diet), as dietary supplements of rats exposed to azomethane (AOM, 20 mg/kg bw), were found to significantly reduce aberrant crypt foci (ACF) in the colon and inclusion of limonoids in the diet at the AOM tumor-induced initiation phase could decrease the incidence of colonic adenocarcinoma (Tanaka et al., 2000, 2001). Obacunone (51) was found to enhance the cytotoxicity of vincristine against L1210 cells by about 10-fold and the cytotoxicity of other microtubule inhibitors such as vinblastine and taxol in drug-sensitive KB-3-1 cells and multidrug-resistant KB-V1 cells (Jung et al., 2000). Quinoline alkaloids are also the major and characteristic components in Dictamnus species. It was found that dictamnine (1) and peskimmianine (34) possess cytotoxic activities against lymphoma L1210 cell line and peskimmianine (34) was most potent with an IC50 value of 3.1 mg/ml (Gao et al., 2011). γfagarine (5) haplopine (5) and skimmianine (9) were found to be cytotoxic against epitheloid cervix carcinoma HeLa cells and the cytotoxic properties of the three furoquinoline alkaloids seem to be correlated with their degree of methoxylation (IC50 skimmianineo IC50 haplopine oIC50 γ-fagarine) (Jansen et al., 2006).

Bioactivity comparison between furoquinoline alkaloids and limonoids revealed that some furoquinoline alkaloids such as dictamnine (1), robustine (3), γ-fagarine (5) and skimmianine (9) displayed significantly stronger cytotoxic activities against breast cancer MCF7 and colon cancer LoVo cells than certain limonoids such as limonin (45), obacunone (51), dictamdiol (73) and isodictamdiol (77) (Lv et al., 2015b). Additionally, dasycarpuside A (166) was found to exhibit weak cytotoxic activity against human lung adenocarcinoma A-549 cell line (Chang et al., 2002). Additionally, the cytotoxicity of the oil from the root bark of Dictamnus dasycarpus on three human breast cancer cell lines was significantly stronger than on other cell lines (Lei et al., 2008) and the oil from the root bark of Dictamnus angustifolius also have significant cytotoxic activities against MCF7 and LoVo cells (Sun et al., 2015b). 4.2. Anti-inflammatory, anti-allergic and immunological activities The lactone extract of the root bark of Dictamnus dasycarpus possess anti-inflammatory effects (Gao et al., 2011). Kim et al. investigated the effects of the methanol extract of the root bark of Dictamnus dasycarpus on ear thickness, ear weights, histopathological changes such as hyperplasia, edema, spongiosis and immune cell infiltration and cytokine productions in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis mice as well as its effects on degranulation of histamine and β-hexosaminidase using RBL-2H3 cells (Kim et al., 2013). The results indicated that the root bark of Dictamnus dasycarpus has the potential to treat allergic skin diseases. Han et al. found that the anti-inflammatory effects of Dictamnus dasycarpus on contact dermatitis are involved in the regulation of Intercellular Adhesion Molecule-1 (ICAM-1) expression and cytokine and chemokine secretion through downregulation of the nuclear factor-kappa B (NF-κB) signaling pathway in keratinocytes (Han et al., 2015). Besides, the anti-inflammatory effect of fraxinellone (65) was found to be associated with the down-regulations of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) due to NF-κB inhibition through the

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

257

Fig. 6. The chemical structures of sesquiterpenes and its glycosides from Dictamnus species.

negative regulations of IkappaB kinase (IKK) and extracellularsignal-related kinase (ERK1/2) phosphorylations in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages (Kim et al., 2009). Jiang et al. investigated the anti-allergic effect of a 70% ethanol extract from Dictamnus dasycarpus in ICR mice and found that the systemic anaphylactic shock induced by compound 48/80 could be inhibited by the extract at doses of 200 and 500 mg/kg. Besides, in an in vitro study, the extract inhibited the histamine released from rat peritoneal mast cells induced by compound 48/80 (Jiang et al., 2008). From the water-soluble of the root bark of Dictamnus dasycarpus, Chang et al. isolated 11 sesquiterpene glycosides and in vitro tests of these compounds for immunological activity showed that dictamnoside A (89, 10  5 mol/L) possessed remarkable activity in stimulating the proliferation of T-cells (Chang et al., 2001). They further discovered that two phenolic glucosides, compounds 163 and 165 (1 mM) could remarkably inhibit the proliferation of T-cells in vitro (Chang et al., 2002). Under the guidance of selecting a new immunosuppressant that selectively deletes pathogenic T cells without affecting non-activated T cells to avoid intervention of normal immune responses to other foreign antigens, Sun et al. found that fraxinellone (65, 7.5 mg/kg twice per day) could treat Tcell-dependent hepatitis in mice by selective triggering apoptosis of concanavalin A-activated T cells (Sun et al., 2009).

4.3. Anti-microbial and anti-HIV activities Zhao et al. found that the dichloromethane extract of the root bark of Dictamnus dasycarpus possess growth inhibition effects against the plant pathogenic fungus Cladosporiurn cucumerinum and further bioactivity-guided isolation revealed that dictamnine (1), haplopine (6), calodendrolide (79), dasycarpol (66), fraxinellone (65), isofraxinellone (68) were found to be active against C. cucumerinum and dictamnine (1) was most potent (0.6 μg on TLC plate). Meanwhile, the structure-activity studies of limonoids and derivatives demonstrated that the region of C and D rings and the attached furan ring seemed to be critical for the growth inhibitory activity against C. cucumerinum and the lactone groups in these compounds were not crucial for the growth inhibitory effect (Zhao et al., 1998b). Lei et al. found that the oil from the root bark of Dictamnus dasycarpus showed the strongest bactericidal activity against Staphylococcus aureus ATCC 25923 and methicillinresistant S. aureus than the other bacterial strains selected (Lei et al., 2008). Sun et al. found that the oil from the root bark of Dictamnus angustifolius showed significant inhibitory effect on Monilia albican ATCC 10231 and Staphylococcus aureus ATCC 6538 (Sun et al., 2015b). Lv et al. found that compared with Dictamnus dasycarpus, the methanolic extract of Dictamnus angustifolius showed a higher antimicrobial activity against the two bacterial

258

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

Fig. 7. The chemical structures of flavones from Dictamnus species.

strains E. coli ATCC 8739 and S. aureus ATCC 6538 with MIC values of 119 mg/ml and 81 mg/ml as well as two fungal strains A. niger ATCC 16404 and M. albican ATCC 10231 with MIC values of 263 mg/ ml and 56 mg/ml, respectively. Besides, furoquinoline alkaloids such as dictamnine (1), robustine (3), γ-fagarine (5) and skimmianine (9) exhibited more significant antimicrobial activities against E. coli ATCC 8739, S. aureus ATCC 6538, A. niger ATCC 16404 and M. albican ATCC 10231 than limonoids such as limonin (45), obacunone (51), dictamdiol (73) and isodictamdiol (77) (Lv et al., 2015b). In the past few years, several plant-derived natural compounds have been screened for their anti-HIV activity in order to find lead compounds with novel structures or mechanisms of action. Among these, several triterpenoids have been found to exhibit an antiretroviral activity with different mechanisms of action. The effect of two limonoids, limonin (45) and nomilin (55), were tested on the growth of human immunodeficiency virus-1 (HIV-1) in culture of human peripheral blood mononuclear cells (PBMC) and on monocytes/macrophages (M/M). It was found that limonin (45) and nomilin (55) could inhibit the HIV-1 replication in all cellular systems used, with EC50 values of 60.0 mM and 52.2 mM, respectively (Battinelli et al., 2003).

4.4. Anti-platelet-aggregation and vascular-relaxing activities Sun et al. isolated three degraded limonoids and six quinoline alkaloids from the root bark of Dictamnus angustifolius and they exhibited significant inhibitory effects on adenosine diphosphate (ADP)-induced blood platelet aggregation with the inhibition value equal or superior at the concentration of 250 μM when compared with aspirin. Additionally, 8-hydroxy-9-methyl-furo [2,3-b]quinolin-4(9 H)-one (19) showed potent anti-platelet aggregation activity (Sun et al., 2013a). Components of Dictamnus dasycarpus were tested for their vascular-relaxing effects on the rat aorta, and fraxinellone (65) and dictamine (1) were shown to be effective vasorelaxants. In high K þ (60 mmol/L) medium, Ca2 þ (0.03 to 3 mmol/L)-induced vasoconstriction was inhibited concentration-dependently by fraxinellone (56) and dictamine (1) with IC50 values of 25 μmol/L and 15 μmol/L (for Ca2 þ concentration of 1 mmol/L), respectively (Yu et al., 1992). The results suggested that fraxinellone was a selective blocker of voltage-dependent Ca2 þ channel, while dictamine relaxed the rat aorta by suppressing the Ca2 þ influx through both voltagedependent and receptor-operated Ca2 þ channels.

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

259

Fig. 8. The chemical structures of coumarins from Dictamnus species.

Fig. 9. The chemical structures of steroids and triterpenes from Dictamnus species.

4.5. Anti-insect activities Currently, the discovery of new insecticidal compounds from plant secondary metabolites and subsequently using them as the lead-compounds for further modification has been one of the important ways for the research and development of new pesticides. The antifeedant activities of fraxinellone (65, 20 mg/ml) have been reported against Oryzias latipes, Spodoptera littoralis, Spodoptera exigua, Mythimna separata, Ostrinia furnacalis and two stored-product insects, Tribolium castaneum and Sitophilus zeamais (Lü et al., 2010). Liu et al. investigated the mode of action of fraxinellone against insects. After treatment with fraxinellone (65) at 300 ppm for 24 h, the activities of α-amylase and non-specific proteases in larval midguts of O. furnacalis reduced, but the activities of cytochrome P450s increased (Liu et al., 2002). Lü et al. investigated the effect of fraxinellone on fifth instar larvae of eastern armyworm, M. separata Walker and deduced that fraxinellone is a new digestive poison that showed the delayed

insecticidal activity, and could obviously affect the epithelium membrane in the midgut of M. separate (Lü et al., 2010). 4.6. Antidepressant and neuroprotective activities Jeong et al. found that the methanol extract (250 μg/ml) from the aerial parts of Dictamnus albus was active in inhibiting monoamine oxidase (MAO) from the mouse brain and activityguided fractionation revealed that two coumarins inhibited MAO activity in a concentration-dependent manner and showed a selective inhibitory effect against MAO-B compared to MAO-A (Jeong et al., 2006). As the representative components in Dictamnus species, limonoids such as limonin (45), obacunone (51), fraxinellone (65), dictamdiol A (74), calodendrolide (79), dictamnusine (81) showed significant neuroprotective activity against glutamate-induced neurotoxicity in primary cultures of rat cortical cells at a concentration of 0.1 μM (Yoon et al., 2008). Yoon et al. further investigated the neuroprotective mechanism of these

260

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

Fig. 10. The chemical structures of other compounds from Dictamnus species.

compounds using the same in vitro culture system and found that obacunone (51), limonin (45), fraxinellone (65), and calodendrolide (79) significantly protect primary culture cortical cells against glutamate-induced toxicity by preserving the antioxidant defense system (Yoon et al., 2010). These compounds may offer potential drug development candidates for various neurodegenerative diseases involved with glutamate. Moreover, the Cu-ascorbate redox system assay revealed that dictangustone B (63) (25 μmol/L) could control Cu(I/II)-triggered hydroxyl radical (OH ) production (2– 50 μmol/L) by halting copper redox cycling via metal complexation. Importantly, dictangustone A (59), B (63), D (61) and F (64) were nontoxicity to SH-SY5Y cells at different concentrations ranging from 1.25 to 10 μM and showed significant neuroprotective activity against neuronal death induced by oxidative stress. Dictangustone B (63) showed the highest protective capability (at 10 μM) almost the same as trolox at the concentration of 3 μM. Taken together, these limonoids such as dictangustone B (63) may be good candidates for developing new drugs in the treatment of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson's disease (Sun et al., 2015a).

by an Ames test using Salmonella typhimurium TA100 and the results showed that the antimutagenic component in Dictamnus dasycarpus was clearly identified as isofraxinellone (68), with an ID50 value of 0.24 μmol/ml and 0.30 μmol/ml, respectively, while fraxinellone (65) had no antimutagenic activity (Miyazawa et al., 1995). The structural difference between isofraxinellone (68) and fraxinellone (65) is the position of the double bond in the cyclohexene ring. Accordingly, they deduced that the presence of a double bond at the 6–7 position is important for antimutagenic activity.

4.7. Antimutagenic activities

Chen et al. tested the free radical-scavenging and antioxidant activity of various solvent extracts of skin of Dictamnus dasycarpus using DPPH, ABTS radical scavenging assay and reducing power tests (Chen et al., 2013). The results revealed that the acetone

Miyazawa et al. tested the antimutagenic activities of fraxinellone (65) and isofraxinellone (68) against furylfuramide and Trp-P-1

4.8. Antifertility activities The hexane fraction of methanol extracts of root bark of Dictamnus albus decreased fertility in rats when administered orally on days 1–10 post-coitum and fractionation of the hexane extract led to isolation of fraxinellone, which exerted antifertility activity through inhibiting implantation (Woo et al., 1987). 4.9. Antioxidant activities

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

extract exhibited outstanding antioxidant activities. Lv et al. found that the methanol extract of Dictamnus angustifolius showed greater radical-scavenging activity and reducing power than of that of Dictamnus dasycarpus due to the presence of higher level of furoquinoline alkaloids in Dictamnus angustifolius (Lv et al., 2015b).

261

Additionally, skimmianine (9), also isolated from the root bark of Dictamnus dasycarpus, was found to be mutagenic towards TA100 (77 revertant colonies per μg) and TA98 (27 revertant colonies per μg) in the presence of S9 mix (Kanamori et al., 1986).

7. Concluding remarks 5. Quality control As described previously, distribution of Dictamnus dasycarpus almost scatters across the country of China and chemical composition may vary with different production areas. In Chinese Pharmacopeia qualitative identification by thin layer chromatography (TIC) and determination of content by high performance liquid chromatography (HPLC) are generally used to evaluate the quality of Cortex Dictamni. Obacunone (51), fraxinellone (65) are chosen as two marker components to control the quality of Cortex Dictamni, and it is required that the content of fraxinellone (65) should be no less than 0.050% and the content of obacunone (51) should be no less than 0.15%. However, the two marker compounds may be insufficient to fully evaluate the quality of Cortex Dictamni due to complex chemical composition and multiple pharmacological activities of herbal medicines. Dictamnus angustifolius only distributes in Xinjiang province of China and has been used as an alternative popular and traditional medicine in local areas. Chemical comparison between the root bark of Dictamnus angustifolius and Dictamnus dasycarpus using plant metabolomics revealed that Dictamnus angustifolius had higher level of major furoquinoline alkaloids and lower level of limonoids than Dictamnus dasycarpus (Lv et al., 2015b). Therefore, more bioactive constituents such as furoquinoline alkaloids should be integrated into the quality control system of Dictamnus species.

Cortex Dictamni has been used to treat eczema, rubella, scabies, acute rheumatoid arthritis, skin inflammation, jaundice, cold, and headache in traditional Chinese medines for thousands of years. Yet further study is still needed to gain a comprehensive understanding of Cortex Dictamni and provide latest information for clinincal staff. Phytochemical investigations indicated that quinoline alkaloids and limonoids were the major bioactive components of the species from genus Dictamnus. Due to their potential cytotoxic, neuroprotective, anti-inflammatory, antimicrobial, antiplatelet-aggregation and vascular relaxing activities, these compounds have attracted great interests in the past few years and may have great potential to be new drug lead compounds. Limonoids may be potential candidates for developing new drugs in the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. However, the possible mechanisms, pharmacokinetics and structure-activity relationship of these limonoids should be further explored. The pharmacological effects and possible mechnisms of other pure compounds are also demanded to clarify. Besides, the potential synergistic or antagonistic effects of multiple components in Dictamnus species need to be evaluated integrating pharmacological, pharmacokinetic and physiological approaches. In addition, further toxicological studies are still needed as the crude extracts and pure compounds from Dictamnus have been reported to possess phototoxic effect and acute liver injury.

6. Toxicology Jang et al. reported four cases of toxic hepatitis that occurred after taking a decoction made by boiling down the root of Dictamnus dasycarpus. The four patients had a median age of 60 years, common symptoms of jaundice and general weakness (Jang et al., 2008). Wang et al. evaluated the safety of Cortex Dictamni aqueous extract by acute and sub-chronic toxicity studies in mice and rats. The acute toxicity of Cortex Dictamni aqueous extract was not clearly observed. However, it is possible that Cortex Dictamni aqueous extract has a selective toxicity given the changes in some hematological and liver function parameters and the liver-body weight ratios in the sub-chronic oral toxicity study (Wang et al., 2014). Schempp et al. (1996), Knuchel and Luderschmidt (1986), Henderson and DesGroseilliers (1984), Szendrei et al. (1968) and Suhonen (1977) reported that furocoumarins and alkaloids in Dictamnus albus may lead to bullous phototoxic contact dermatitis, leaving behind long lasting postinflammatory hyperpigmentations. Schempp et al. investigated the phototoxic effect of dictamnine (1) in human Jurkat T cells and HaCaT keratinocytes and they found that dictamnine displayed concentration- and lightdependent phototoxic effects in both cell lines (Schempp et al., 2006). Although dictamnine was less phototoxic compared with structurally related furocoumarins 5-methoxypsoralen and 8-methoxypsoralen, it may play a major role in the elicitation of phytophotodermatitis due to its abundance in plants of the Rutaceae family. It was also reported that dictamnine (1) and γ-fagarine (5) were mutagenic in strain TA100 (50 and 70 revertant colonies per μg, respectively) and TA98 (30 and 50 revertant colonies per μg, respectively) with S9 mix (Mizuta and Kanamori, 1985).

Acknowledgments This study was financially supported by the National Science Foundation of China (No. 81302733), the research project of Chinese Ministry of education (No. 113036A), the Program for Jiangsu province Innovative Research Team, the Program for New Century Excellent Talents in University (No. NCET-13–1036), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Fundamental Research Funds for the Central Universities (No. JKZD2013004) and the Open Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (Nos. SKLNMZZYQ201303 and SKLNMKF201220) References Akhmedzhanova, V.I., Bessonova, I.A., Yunusov, S.Y., 1978. The roots of Dictamnus angustifolius. Chem. Nat. Compd. 14, 404–406. Asatiani, V.S., Kikvidze, I.M., Bessonova, I.A., Mudzhipi, K.S., Yunusov, S.Y., 1971. Alkaloids of fraxinella, Dictamnus caucasicus Fisch, gamma-phagarine, 6,8dimethoxyisodictamnine, 6-methoxyisodictamnine, robustine, and isodictamnine. Soobshch. Akad. Nauk Gruz. SSR 64, 85–88. Battinelli, L., Mengoni, F., Lichtner, M., Mazzanti, G., Saija, A., Mastroianni, C.M., Vullo, V., 2003. Effect of limonin and nomilin on HIV-1 replication on infected human mononuclear cells. Planta Med. 69, 910–913. Bodalski, T., Malcher, E., 1964. Detection and determination of rutin in the leaves of Dictamnus albus. Acta Pol. Pharm. 21, 51–54. Chang, J., Xuan, L.J., Xu, Y.M., Zhang, J.S., 2002. Cytotoxic terpenoid and immunosuppressive phenolic glycosides from the root bark of Dictamnus dasycarpus. Planta Med. 68, 425–429. Chang, J., Xuan, L.J., Xu, Y.M., Zhang, J.S., 2001. Seven new sesquiterpene glycosides from the root bark of Dictamnus dasycarpus. J. Nat. Prod. 64, 935–938. Chen, J., Tang, J.S., Tian, J., Wang, Y.P., Wu, F.E., 2000. Dasycarine, a new quinoline alkaloid from Dictamnus dasycarpus. Chin. Chem. Lett. 11, 707–708.

262

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

Chen, R., Su, W., Li, P.Y., Huo, L.N., Lu, R.M., Peng, M.P., 2013. Free radical-scavenging and antioxidant activity of skin of Dictamnus dasycarpus. Asian J. Chem. 25, 1753–1754. Chinese Herbalism Editorial Board, State Administration of Traditional Chinese Medicine of the People's Republic of China, 1999. Zhong Hua Ben Cao. 4. Shanghai Science and Technology Press, pp. 921–924. Denisova, G.A., Belenovskaya, L.M., 1972. Localization of coumarin compounds in secretory vessels of the aboveground organs of Dictamnus gymnostylis. Tr. Bot. Inst., Akad. Nauk SSSR, Ser. 5 (16), 10–23. Du, C.F., Yang, X.X., Tu, P.F., 2005. Studies on chemical constituents in bark of Dictamnus dasycarpus. China J. Chin. Mater. Med. 30, 1663–1666, in Chinese. Gao, X., Zhao, P.H., Hu, J.F., 2011. Chemical constituents of plants from the genus Dictamnus. Chem. Biodivers. 8, 1234–1244. Gellert, M., Novak, I., Szendrei, K., Reisch, J., Minker, E., 1971. Quinoline alkaloids of Dictamnus albus. Herba Hung. 10, 123–130. Gonzalez, A.G., Diaz, C.E., Lopez, D.H., Luis, J.R., Rodriguez, L.F., 1977. New sources of natural coumarins. XXX. Chemical components of “Ruta chalepensis” L. and “Dictamnus hispanicus” Webb. An. Quim. 73, 430–438. Grabarczyk, H., 1964. Flavonoid compounds in the leaves and influorescence of Dictamnus albus. Diss. Pharm. 16, 177–182. Guo, L.N., Pei, Y.H., Chen, G., Cong, H., Liu, J.C., 2012a. Two new compounds from Dictamnus dasycarpus. J. Asian Nat. Prod. Res. 14, 105–110. Guo, L.N., Pei, Y.H., Chen, G., Lu, X., Xu, H., Liu, J.C., 2012b. Three new compounds from Dictamnus dasycarpus. J. Asian Nat. Prod. Res. 14, 210–215. Han, H.Y., Ryu, M.H., Lee, G., Cheon, W.J., Lee, C., Kim, W.G., Cho, S.I., H., 2015. Effects of Dictamnus dasycarpus Turcz., root bark on ICAM-1 expression and chemokine productions in vivo and vitro study. J. Ethnopharmacol. 159, 245–252. Henderson, J.A., DesGroseilliers, J.P., 1984. Gas plant (Dictamnus albus) phytophotodermatitis simulating poison ivy. Can. Med. Assoc. J. 130, 889–891. Hu, C.Q., Han, J.W., Zhao, J.G., Song, G.Q., Li, Y.H., Yin, D.X., 1989. Limonoids from Dictamnus angustifolius. Zhiwu Xuebao 31, 453–458, in Chinese. Ivanova, A., Kostova, I., Mikhova, B., Vitkova, A., 2004. Chemical components of Dictamnus albus L. Dokl. Bulg. Akad. Nauk. 57, 45–48. Jang, J.S., Seo, E.G., Han, C., Chae, H.B., Kim, S.J., Lee, J.D., Wang, J.H., 2008. Four cases of toxic liver injury associated with Dictamnus dasycarpus. Korean J. Hepatol. 14, 206–212. Jansen, O., Akhmedjanova, V., Angenot, L., Balansard, G., Chariot, A., Ollivier, E., Tits, M., Frédérich, M., 2006. Screening of 14 alkaloids isolated from Haplophyllum A. Juss. for their cytotoxic properties. J. Ethnopharmacol. 105, 241–245. Jeong, G.S., Byun, E., Li, B., Lee, D.S., An, R.B., Kim, Y.C., 2010. Neuroprotective effects of constituents of the root bark of Dictamnus dasycarpus in mouse hippocampal cells. Arch. Pharma. Res. 33, 1269–1275. Jeong, S.H., Han, X.H., Hong, S.S., Hwang, J.S., Hwang, J.H., Lee, D., Lee, M.K., Ro, J.S., Hwang, B.Y., 2006. Monoamine oxidase inhibitory coumarins from the aerial parts of Dictamnus albus. Arch. Pharm. Res. 29, 1119–1124. Jiang, S., Nakano, Y., Rahman, M.A., Yatsuzuka, R., Kamei, C., 2008. Effects of a Dictamnus dasycarpus T. extract on allergic models in mice. Biosci. Biotechnol. Biochem. 72, 660–665. Jiang, Y., Li, S.P., Chang, H.T., Wang, Y.T., Tu, P.F., 2006a. Pressurized liquid extraction followed by high-performance liquid chromatography for determination of seven active compounds in Cortex Dictamni. J. Chromatogr. A 1108, 268–272. Jiang, Y., Tu, P.F., Zhang, N., 2006b. Assignment of 1H and 13C chemical shifts of dictamdiol. Bopuxue Zazhi 23, 327–332, in Chinese. Yang, J.L., Liu, L.L., Shi, Y.P., 2011. Limonoids and quinoline alkaloids from Dictamnus dasycarpus. Planta Med. 77, 6. Jung, H.J., Sok, D.E., Kim, Y.H., Min, B.S., Lee, J.P., Bae, K.H., 2000. Potentiating effect of obacunone from Dictamnus dasycarpus on cytotoxicity of microtuble inhibitors, vincristine, vinblastine and taxol. Planta Med. 66, 74–76. Kanamori, H., Sakamoto, I., Mizuta, M., 1986. Further study on mutagenic furoquinoline alkaloids of dictamni radicis cortex: isolation of skimmianine and highperformance liquid chromatographic analysis. Biol. Pharm. Bull. 34, 1826–1829. Kim, H., Kim, M., Kim, H., Lee, G.S., Cho, S.I., W.G., 2013. Anti-inflammatory activities of Dictamnus dasycarpus Turcz., root bark on allergic contact dermatitis induced by dinitrofluorobenzene in mice. J. Ethnopharmacol. 149, 471–477. Kim, J.H., Park, Y.M., Shin, J.S., Park, S.J., Choi, J.H., Jung, H.J., Park, H.J., Lee, K.T., 2009. Fraxinellone inhibits lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 expression by negatively regulating nuclear factor-kappa B in RAW 264.7 macrophages cells. Biol. Pharm. Bull. 32, 1062–1068. Kim, S.W., Yeo, W.H., Ko, Y.S., Kim, S.K., 1997. Isolation and characterization of antitumor agents from Dictamnus albus. Saengyak Hakhoechi 28, 209–214. Knuchel, M., Luderschmidt, C., 1986. Bullous phototoxic contact dermatitis caused by Dictamnus albus. The Bible's “burning bush”? Dtsch Med Wochenschr 111, 1445–1447. Komissarenko, N.F., Levashova, I.G., Akhmedov, U.A., 1984. Coumarins and flavonoids of Dictamnus angustifolius. Khim. Prir. Soedin., 247–248. Lü, M., Wu, W., Liu, H., 2010. Effects of fraxinellone on the midgut ultrastructural changes of Mythimna separata Walker. Pestic. Biochem. Phys. 98, 263–268. Lam, L.K.T., Zhang, J., Hasegawa, S., 1994a. Citrus limonoid reduction of chemically induced tumorigenesis. Food Technol. 48, 104–108. Lam, L.K.T., Zhang, J., Hasegawa, S., Schut, H.A., 1994b. Inhibition of chemically induced carcinogenesis by citrus limonoids. ACS Symposium Series (USA). Lei, J.C., Yu, J.Q., Yu, H.D., Liao, Z.H., 2008. Composition, cytotoxicity and antimicrobial activity of essential oil from Dictamnus dasycarpus. Food Chem. 107, 1205–1209.

Li, X., Tang, H.Z., Gou, X.J., Tu, J., 2008. Study on chemical constituents of the root of Dictamnus dasycarpus. Zhongyaocai 31, 1816–1819, in Chinese. Lin, T.P., Shieh, B., 1986. Furoquinoline alkaloids from Pai-Shen Pi (Dictamnus dasycarpus Turcz) in Rutaceae. Hua Hsueh 44, 96–100. Liu, Z.L., Xu, Y.J., Wu, J., Goh, S.H., Ho, S.H., 2002. Feeding deterrents from Dictamnus dasycarpus Turcz against two stored-product insects. J. Agr. Food Chem. 50, 1447–1450. Lu, M., Wu, W.J., Liu, H.X., 2013. Insecticidal and feeding deterrent effects of fraxinellone from Dictamnus dasycarpus against four major pests. Molecules 18, 2754–2762. Lv, M.Y., Tang, B.Q., Teng, J., Liang, J.Y., Xu, F.G., Zhang, Z.J., Sun, J.B., 2015a. Chemotaxonomic significance of limonoids and triterpenoids from Dictamnus angustifolius G. Don ex Sweet. Biochem. Syst. Ecol. , http://dx.doi.org/10.1016/j. bse.2015.02.015. Lv, M.Y., Tian, Y., Zhang, Z.J., Liang, J.Y., Xu, F.G., Sun, J.B., 2015b. Plant metabolomics driven chemical and biological comparison of the root bark of Dictamnus dasycarpus and Dictamnus angustifolius. RSC Adv. 5, 15700–15708. Manners, G.D., 2007. Citrus limonoids: analysis, bioactivity, and biomedical prospects. J. Agr. Food Chem. 55, 8285–8294. Miller, E.G., Fanous, R., Rivera-Hidalgo, F., Binnie, W.H., Hasegawa, S., Lam, L.K.T., 1989. The effects of citrus limonoids on hamster buccal pouch carcinogenesis. Carcinogenesis 10, 1535–1537. Miyazawa, M., Shimamura, H., Nakamura, S., Kameoka, H., 1995. Antimutagenic activity of isofraxinellone from Dictamnus dasycarpus. J. Agr. Food Chem. 43, 1428–1431. Mizuta, M., Kanamori, H., 1985. Mutagenic activities of dictamnine and gammafagarine from dictamni radicis cortex (Rutaceae). Mutation Res. 144, 221–225. Nam, K.W., Je, K.H., Shin, Y.J., Kang, S.S., Mar, W., 2005. Inhibitory effects of furoquinoline alkaloids from Melicope confusa and Dictamnus albus against human phosphodiesterase 5 (hPDE5A) in vitro. Arch. Pharm. Res. 28, 675–679. Reisch, J., Szendrei, K., Minker, E., Novak, I., 1967. Field of natural products chemistry. XVII. Occurrence of auraptene in Dictamnus albus. Planta Med. 15, 320–322. Renner, W., 1962. Biogenesis of secondary plant substances in Dictamnus albus. Pharmazie 17, 763–776. Roy, A., Saraf, S., 2006. Limonoids: overview of significant bioactive triterpenes distributed in plants kingdom. Biol. Pharm. Bull. 29, 191–201. Schempp, C.M., Simon-Haarhaus, B., Krieger, R., Simon, J.C., 2006. Solar simulatorinduced phototoxicity of the furoquinoline alkaloid dictamnine compared to 8methoxypsoralen and 5-methoxypsoralen. Planta Med. 72, 941–943. Schempp, C.M., Sonntag, M., Schöpf, E., Simon, J.C., 1996. Dermatitis bullosa striata pratensis durch Dictamnus albus L.(Brennender Busch). Der Hautarzt 47, 708–710. Yu, S.M., Ko, F.N., Su, M.J., Wu, T.S., Wang, M.L., Huang, T.F., Teng, C.M., 1992. Vasorelaxing effect in rat thoracic aorta caused by fraxinellone and dictamine isolated from the Chinese herb Dictamnus dasycarpus Turcz: comparison with cromakalim and Ca2 þ channel blockers. Naunyn-Schmiedeberg's Arch. Pharmacol. 345, 349–355. Souleles, C., 1989a. Flavonoids from Dictamnus albus. Planta Med. 55, 402. Souleles, C., 1989b. A new flavonoid glycoside from Dictamnus albus. J. Nat. Prod. 52, 1311–1312. Storer, R., Young, D., 1973. Constituents of the root of Dictamnus albus L. Tetrahedron 29, 1217–1222. Suhonen, R., 1977. Phytophotodermatitis: an experimental study using the chamber method. Contact Dermat. 3, 127–132. Sultanov, S.A., Yunusov, S.Y., 1969. Alkaloids of Dictamnus angustifolius. Khim. Prir. Soedin. 5, 195–196. Sun, J.B., Jiang, N., Lv, M.Y., Wang, P., Xu, F.G., Liang, J.Y., Qu, W., 2015a. Limonoids from the root bark of Dictamnus angustifolius: potent neuroprotective agent with biometal chelation, halting copper redox cycling properties. RSC Adv. 5, 24750–24757. Sun, J.B., Qu, W., Wang, P., Wu, F.H., Wang, L.Y., Liang, J.Y., 2013a. Degraded limonoids and quinoline alkaloids from Dictamnus angustifolius G. Don ex Sweet. and their anti-platelet aggregation activity. Fitoterapia 90, 209–213. Sun, J.B., Qu, W., Xiong, Y., Liang, J.Y., 2013b. Quinoline alkaloids and sesquiterpenes from the roots of Dictamnus angustifolius. Biochem. Syst. Ecol. 50, 62–64. Sun, J.B., Wang, X.Z., Wang, P., Li, L.Z., Qu, W., Liang, J.Y., 2015b. Antimicrobial, antioxidant and cytotoxic properties of essential oil from Dictamnus angustifolius. J. Ethnopharmacol. 159, 296–300. Sun, Y., Qin, Y., Gong, F.Y., Wu, X.F., Hua, Z.C., Chen, T., Xu, Q., 2009. Selective triggering of apoptosis of concanavalin A-activated T cells by fraxinellone for the treatment of T-cell-dependent hepatitis in mice. Biochem. Pharmacol. 77, 1717–1724. Szendrei, K., Novak, I., Varga, E., Buzas, G., 1968. On the active materials of Dictamuus albus L. 1. Photodynamic materials. Pharmazie 23, 76–77. Takeuchi, N., Fujita, T., Goto, K., Morisaki, N., Osone, N., Tobinaga, S., 1993. Dictamnol, a new trinor-guaiane type sesquiterpene, from the roots of Dictamnus dasycarpus Turcz. Chem. Pharm. Bull. 41, 923–925. Tanaka, T., Kohno, H., Tsukio, Y., Honjo, S., Tanino, M., Miyake, M., Wada, K., 2000. Citrus limonoids obacunone and limonin inhibit azoxymethane-induced colon carcinogenesis in rats. Biofactors 13, 213–218. Tanaka, T., Maeda, M., Kohno, H., Murakami, M., Kagami, S., Miyake, M., Wada, K., 2001. Inhibition of azoxymethane-induced colon carcinogenesis in male F344 rats by the citrus limonoids obacunone and limonin. Carcinogenesis 22, 193–198.

M. Lv et al. / Journal of Ethnopharmacology 171 (2015) 247–263

Wang, H.P., 2006. Study on chemical components of Cortex Dictamni. Zhongguo Xiandai Yingyong Yaoxue 23, 200–201, in Chinese. Wang, L.L., Li, Z.Q., Li, L.L., Li, Y.L., Yu, M., Zhou, Y.F., Lv, X.Y., Arai, H., Xu, Y., 2014. Acute and sub-chronic oral toxicity profiles of the aqueous extract of Cortex Dictamni in mice and rats. J. Ethnopharmacol. 158 (Part A), 207–215. Wang, P., Sun, J.B., Gao, E.Z., Zhao, Y.L., Qu, W., Yu, Z.G., 2013a. Simultaneous determination of limonin, dictamnine, obacunone and fraxinellone in rat plasma by a validated UHPLC-MS/MS and its application to a pharmacokinetic study after oral administration of Cortex Dictamni extract. J. Chromatogr. B 928, 44–51. Wang, P., Sun, J.B., Xu, J.Y., Gao, E.Z., Yan, Q., Qu, W., Zhao, Y.L., Yu, Z.G., 2013b. Pharmacokinetics, tissue distribution and excretion study of dictamnine, a major bioactive component from the root bark of Dictamnus dasycarpus Turcz. (Rutaceae). J. Chromatogr. B 942–943, 1–8. Wang, Z., Xu, F., An, S., 1992. Chemical constituents from the root bark of Dictamnus dasycarpus Turcz. China J. Chin. Mater. Med. 17, 551–576, in Chinese. Weryszko-Chmielewska, E., Baj, T., Wolski, T., 1998. Structure of secretory tissues and content of some biologically active compounds in flowers and herb of dittany (Dictamnus albus L.). Herba Pol. 44, 361–370. Woo, W.S., Kang, S.S., 1985. Furoquinoline alkaloids in Dictamnus albus root bark. Saengyak Hakhoechi 16, 125–128. Woo, W.S., Lee, E.B., Kang, S.S., Shin, K.H., Chi, H.J., 1987. Antifertility principle of Dictamnus albus root bark. Planta Med. 53, 399–401. Wu, T.S., Li, C.Y., Leu, Y.L., Hu, C.Q., 1999. Limonoids and alkaloids of the root bark of Dictamnus angustifolius. Phytochemistry 50, 509–512.

263

Wu, T.S., Wang, M.L., Shyur, H.J., Leu, Y.L., Chan, Y.Y., Teng, C.M., Kuo, S.C., 1994. Chemical constituents and bioactive principles from the root bark of Dictamnus dasycarpus. Chin. Pharm. J. (Taipei) 46, 447–455. Yoon, J.S., Jeong, E.J., Yang, H., Kim, S.H., Sung, S.H., Kim, Y.C., 2012. Inhibitory alkaloids from Dictamnus dasycarpus root barks on lipopolysaccharide-induced nitric oxide production in BV2 cells. J. Enzym. Inhib. Med. Chem. 27, 490–494. Yoon, J.S., Sung, S.H., Kim, Y.C., 2008. Neuroprotective limonoids of root bark of Dictamnus dasycarpus. J. Nat. Prod. 71, 208–211. Yoon, J.S., Yang, H., Kim, S.H., Sung, S.H., Kim, Y.C., 2010. Limonoids from Dictamnus dasycarpus protect against glutamate-induced toxicity in primary cultured rat cortical cells. J. Mol. Neurosci. 42, 9–16. Zhao, P.H., Sun, L.M., Cao, M.A., Yuan, C.S., 2007. Two limonoids from the root of Dictamnus radicis Cortex. Chem. Lett. 36, 1200–1201. Zhao, W.M., Wang, S.C., Qin, G.W., Xu, R.S., Hostettmann, K., 2001. Dictamnosides F and G-two novel sesquiterpene diglycosides with α-configuration glucose units from Dictamnus dasycarpus. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 40B, 748–750. Zhao, W.M., Wolfender, J.L., Hostettmann, K., Li, H.Y., Stoeckli-Evans, H., Xu, R.S., Qin, G.W., 1998a. Sesquiterpene glycosides from Dictamnus dasycarpus. Phytochemistry 47, 63–68. Zhao, W.M., Wolfender, J.L., Hostettmann, K., Xu, R.S., Qin, G.W., 1998b. Antifungal alkaloids and limonoid derivatives from Dictamnus dasycarpus. Phytochemistry 47, 7–11.